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White matter loss in a mouse model of periventricular leukomalacia is rescued by trophic factors.

Espinosa-Jeffrey A, Barajas SA, Arrazola AR, Taniguchi A, Zhao PM, Bokhoor P, Holley SM, Dejarme DP, Chu B, Cepeda C, Levine MS, Gressens P, Feria-Velasco A, de Vellis J - Brain Sci (2013)

Bottom Line: In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly.Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA).Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs).

View Article: PubMed Central - PubMed

Affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. aespinosa@mednet.ucla.edu.

ABSTRACT
Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.

No MeSH data available.


Related in: MedlinePlus

Neuroprotection of Medium-sized Spiny Neurons (MSNs). Upper traces represent responses of striatal MSNs evoked by electrical stimulation (0.2 mA, 0.1 ms duration) of cortical inputs. Recordings were obtained with patch electrodes in voltage clamp mode (holding voltage at +40 mV). Control trace is a NMDA receptor-mediated response recorded in normal ACSF solution and isolated pharmacologically by adding 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX, 10 μM) and Bicuculline (10 μM). The trace on the right is from another cell recorded after the slice was incubated for 1 h in TSC1 solution (2 μL/mL). Lower traces show responses to bath application of NMDA (100 μM) in ACSF (left) or after incubation for 1 h in TSC-1. Notice that the NMDA responses were significantly reduced compared to control conditions. Calibration bars apply to both traces.
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brainsci-03-01461-f005: Neuroprotection of Medium-sized Spiny Neurons (MSNs). Upper traces represent responses of striatal MSNs evoked by electrical stimulation (0.2 mA, 0.1 ms duration) of cortical inputs. Recordings were obtained with patch electrodes in voltage clamp mode (holding voltage at +40 mV). Control trace is a NMDA receptor-mediated response recorded in normal ACSF solution and isolated pharmacologically by adding 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX, 10 μM) and Bicuculline (10 μM). The trace on the right is from another cell recorded after the slice was incubated for 1 h in TSC1 solution (2 μL/mL). Lower traces show responses to bath application of NMDA (100 μM) in ACSF (left) or after incubation for 1 h in TSC-1. Notice that the NMDA responses were significantly reduced compared to control conditions. Calibration bars apply to both traces.

Mentions: Coronal slices were exposed to either NMDA alone or pre-incubated for 1 h to 2 h in TSC1 and subsequently exposed to NMDA. After electrophysiology as shown (Figure 5), slices were fixed and examined through double immunofluorescence for the cell stress marker heat shock protein 90 (HSP-90) and the OL marker cyclic nucleotide 3′-phosphohydrolase (CNPase). The results showed that HSP-90 was expressed in the CC white matter in NMDA-treated mice but not in non-treated slices (Figure 6A–D vs.Figure 6E–L respectively). Those slices that were pre-incubated with TSC1 presented a clear expression of HSP-90 at the level of the cell soma and processes but not along axonal fibers. CNPase expression was observed and not all CNPase positive cells expressed HSP-90. In contrast, slices treated with NMDA without pre-incubation in TSC1 showed a diffuse distribution of HSP-90 preferentially along the fibers expressed in mini-compartments like “puncta” and only few inter-fascicular cells were clearly seen expressing this stress protein but not CNPase (Figure 6F,G).


White matter loss in a mouse model of periventricular leukomalacia is rescued by trophic factors.

Espinosa-Jeffrey A, Barajas SA, Arrazola AR, Taniguchi A, Zhao PM, Bokhoor P, Holley SM, Dejarme DP, Chu B, Cepeda C, Levine MS, Gressens P, Feria-Velasco A, de Vellis J - Brain Sci (2013)

Neuroprotection of Medium-sized Spiny Neurons (MSNs). Upper traces represent responses of striatal MSNs evoked by electrical stimulation (0.2 mA, 0.1 ms duration) of cortical inputs. Recordings were obtained with patch electrodes in voltage clamp mode (holding voltage at +40 mV). Control trace is a NMDA receptor-mediated response recorded in normal ACSF solution and isolated pharmacologically by adding 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX, 10 μM) and Bicuculline (10 μM). The trace on the right is from another cell recorded after the slice was incubated for 1 h in TSC1 solution (2 μL/mL). Lower traces show responses to bath application of NMDA (100 μM) in ACSF (left) or after incubation for 1 h in TSC-1. Notice that the NMDA responses were significantly reduced compared to control conditions. Calibration bars apply to both traces.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061895&req=5

brainsci-03-01461-f005: Neuroprotection of Medium-sized Spiny Neurons (MSNs). Upper traces represent responses of striatal MSNs evoked by electrical stimulation (0.2 mA, 0.1 ms duration) of cortical inputs. Recordings were obtained with patch electrodes in voltage clamp mode (holding voltage at +40 mV). Control trace is a NMDA receptor-mediated response recorded in normal ACSF solution and isolated pharmacologically by adding 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX, 10 μM) and Bicuculline (10 μM). The trace on the right is from another cell recorded after the slice was incubated for 1 h in TSC1 solution (2 μL/mL). Lower traces show responses to bath application of NMDA (100 μM) in ACSF (left) or after incubation for 1 h in TSC-1. Notice that the NMDA responses were significantly reduced compared to control conditions. Calibration bars apply to both traces.
Mentions: Coronal slices were exposed to either NMDA alone or pre-incubated for 1 h to 2 h in TSC1 and subsequently exposed to NMDA. After electrophysiology as shown (Figure 5), slices were fixed and examined through double immunofluorescence for the cell stress marker heat shock protein 90 (HSP-90) and the OL marker cyclic nucleotide 3′-phosphohydrolase (CNPase). The results showed that HSP-90 was expressed in the CC white matter in NMDA-treated mice but not in non-treated slices (Figure 6A–D vs.Figure 6E–L respectively). Those slices that were pre-incubated with TSC1 presented a clear expression of HSP-90 at the level of the cell soma and processes but not along axonal fibers. CNPase expression was observed and not all CNPase positive cells expressed HSP-90. In contrast, slices treated with NMDA without pre-incubation in TSC1 showed a diffuse distribution of HSP-90 preferentially along the fibers expressed in mini-compartments like “puncta” and only few inter-fascicular cells were clearly seen expressing this stress protein but not CNPase (Figure 6F,G).

Bottom Line: In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly.Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA).Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs).

View Article: PubMed Central - PubMed

Affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. aespinosa@mednet.ucla.edu.

ABSTRACT
Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.

No MeSH data available.


Related in: MedlinePlus